This K23 application, titled "Functional and Structural Neuroanatomy in Late-Life Generalized Anxiety Disorder" represents the revision of 1 K23 MH086686-1. By 2030 as many as 20% of older Americans will meet the diagnostic criteria for an anxiety disorder. Generalized Anxiety Disorder (GAD) is the most prevalent anxiety disorder in the elderly, but it remains one of the most underdiagnosed and less studied mental disorders. It is well known that the aging brain experiences neuroanatomical change, and it has been observed that the incidence of GAD increases in the elderly. Taken together, these statements suggest that different pathophysiological pathways may be involved in late-life GAD. There is a striking discrepancy between the notable public health impact of late-life GAD and the paucity of literature describing its neuroanatomical basis. To date, there has been no neuroimaging research in late-life GAD although late-life GAD offers a good platform for translational research in aging, allowing for mechanistic inferences regarding the role of emotional control networks and the effect of impaired connectivity in the disruption of these networks. The applicant is a geriatric psychiatrist who aspires to become an independent investigator in affective cognitive neuroscience. She is a Research Assistant Professor working in the Advanced Center for Interventions and Services Research for Late-life Mood Disorders (ACISR) at the University of Pittsburgh. She obtained her board certification after completing her residency and clinical fellowship at the Western Psychiatric Institute and Clinic at the University of Pittsburgh. From 2006 she has been first author on 11 publications in peer- reviewed journals and co-authored four additional papers. Dr. Andreescu's overall career goal is to become an independent translational scientist, focused on the affective and cognitive neuroscience of late-life anxiety disorders. This area of research will seek to integrate the functional neural circuits relevant to anxious apprehension with the neurobiology of age-related changes. Her K23 career development goals comprise: 1) Gain advanced knowledge in the affective and cognitive neuroscience of late-life anxiety disorders;2) Develop skills and experience in the acquisition and processing of structural and functional MRI data in older adults;3) Gain knowledge in the imaging genetics of late-life anxiety disorders;4) Strengthen knowledge of study design and statistical methods for geriatric clinical research. Her long-term career goals include 1) developing into an independent investigator in the neuroscience of late-life anxiety and 2) extending affective and cognitive neuroscience constructs and tools to improve treatment outcomes of late-life anxiety. This K23 application details an educational and mentored training program that integrates guided didactics, consultations with experts and a research study focused on late-life GAD. The didactic training will address functional and structural neuroanatomy, affective and cognitive neuroscience, imaging genetics, intervention study design, and the ethical conduct of research. This mentored training period will allow the applicant to gain expertise in neuroimaging in the elderly and generate pilot data for a future definitive study. The details of the mentored research project acknowledge the tenet that pathological anxiety involves the dysregulation of the amygdala-anterior cingulate cortex (ACC) axis. Whereas pediatric and midlife GAD are characterized by a hyperactive amygdala, we posit that the pathophysiological changes in late-life GAD are related to the poor modulatory interplay between the frontal and the limbic structures stemming from age- related disconnectivity. The applicant intends to examine this model by applying a personalized worry probe that explores the dynamic interplay of the amygdala and the subgenual ACC in the induction and maintenance of worry in the elderly. The specific age-related structural abnormalities will be examined in the white matter tracts connecting the amygdala and the anterior cingulate cortex with T2-weighted FLAIR MR images and Diffusion Tensor Imaging (DTI). The applicant will also conduct an exploratory analysis of the genetic correlates of functional neuroanatomic changes in late-life GAD. Specific Aims and Hypothesis Aim 1. Characterize the functional neuroanatomy of late-life generalized anxiety disorder. Hypothesis 1: Compared to non-anxious elderly comparison subjects, late-life GAD subjects will present with: (1) decreased resting state functional connectivity in the default-mode network;(2) increased activation of the amygdala, subgenual ACC and insula during an affective reactivity task;and (3) decreased limbic- prefrontal functional connectivity during both worry induction and worry suppression. Aim 2. Characterize the relationship between functional neuroanatomic changes and structural brain changes in late-life generalized anxiety disorder. Hypothesis 2: Compared with non-anxious elderly subjects, late-life GAD subjects will have a greater burden of white matter abnormalities. This burden of white matter abnormalities will correlate with decreased functional connectivity in the both the default-mode network and the limbic-prefrontal circuit. Aim 3 (exploratory): Identify genetic correlates of functional neuroanatomic changes in late- life generalized anxiety disorder. Hypothesis 3: Late-life GAD subjects with a 5-HTTLPR S allele will present more sustained amygdala activation during worry suppression and a decreased functional connectivity of the amygdala-sACC circuit compared with late-life GAD subjects who are LL homozygotes. This project is novel in three ways: (1) it examines an understudied population burdened by high rates of generalized anxiety;(2) it correlates functional disconnectivity with age-related structural abnormalities;and (3) it uses a functional imaging paradigm (fMRI) designed to elicit the specific emotional processes of GAD. Generating neural signatures corresponding to clinical constructs represents a first step in the direction of tailoring more efficacious and personalized treatments for elderly patients with GAD. This developmental program initiates an integrative strategy for the long-term goal of bridging psychopathology and treatment response with the neuroanatomy of late-life anxiety disorders. PUBLIC HEALTH RELEVANCE: This research project addresses the structural and functional neuroanatomy in Late-Life Generalized Anxiety Disorder, the most prevalent, yet the most underdiagnosed and less studied anxiety disorder in the elderly. The project uses a functional imaging paradigm (fMRI) designed to elicit the specific emotional processes of GAD, and examines the interplay between the frontal and the limbic structures during worry modulation. Generating neural signatures corresponding to clinical constructs such as pathological worry represents a first step in the direction of tailoring more efficacious and personalized treatments for elderly patients with GAD.